Measurement of the efficacy of hemodialysis treatments is currently time consuming, inaccurate and expensive. Approximately 260,000 Americans suffer from end-stage renal disease (ESRD). Fifty-nine percent are treated by thrice-weekly maintenance hemodialysis sessions designed to clear the products of metabolism that are normally excreted by the kidneys in the urine. Since the failure to adequately dialyze a patient has been shown to increase mortality and morbidity and since the process of dialyzing an ESRD patient is complex and variable in terms of the efficiency of the treatment, a number of methods have been developed to quantify the effectiveness of the treatment. The technique used in the overwhelming majority of dialysis centers is based on pre- and post-dialysis measurements of blood urea nitrogen concentrations. Urea, a low-molecular weight molecule, is a product of protein metabolism that is normally cleared from the body by the kidneys. Because it is also cleared from the blood by the dialysis process and easily measured in blood, its disappearance from the blood during hemodialysis is a measure of the efficacy or adequacy of that particular treatment session. The process of removal of toxins from the body by hemodialysis is best represented as a logarithmic function. As such, the coefficient of the natural logarithm termed KT/Vd, which is calculated from pre- and post-dialysis measurements of blood urea concentrations, can be used as a single descriptor of dialysis adequacy.
The importance of adequate duration or dose of hemodialysis has been underscored recently by the observation that the adjusted mortality of patients with renal disease in the United States exceeds that of several other countries, despite a longer life expectancy of the general population of the United States. A number of studies have documented the failure to deliver an adequate dose of hemodialysis to many Americans. The failure of delivery of adequate hemodialysis doses in the United States is a result of many factors. Time and financial pressures contribute to the problem. Because the metabolic toxins are removed from the blood, which makes up only a fraction of the total volume of the body in which the toxins are distributed, there are delays as the solutes redistribute and equilibrate after dialysis. Thus, measurement of KT/Vd is highly dependent on the time of the urea measurements and the relative size of the compartments such as blood water, interstitial water and intracellular water, all of which harbor urea and other contaminants. These compartments vary in size from patient to patient, and within a patient depending upon present physiologic state. The best measure of the post-dialysis urea is made at least 15 minutes after hemodialysis, but for some patients it may require 50 to 60 minutes to reach equilibrium. There is no accurate way to predict which patients will have a significant blood urea increase following hemodialysis at any given treatment time. Given the time constraints on out-patient hemodialysis centers that commonly are able to dialyze no more than two patients per day on a single machine, one in the morning and one in the afternoon, the need to obtain post-dialysis blood urea concentrations 30 to 60 minutes after dialysis is impractical at best. Finally, the late blood measurement requires an additional venipuncture of the patient who is disconnected from the dialysis machine minutes after cessation of circulation through the machine.
Urea testing is a capital burden on the dialysis centers that provide dialysis to ESRD patients under a capitated reimbursement basis. The blood drawing process is labor intensive and exposes the nursing staff to blood borne pathogens. The samples must then be transported to a laboratory for analysis, incurring another charge and a delay in reported values. Currently, the accepted "standard of care" given financial constraints is that KT/Vd be measured once per month, that is, once during every 12 dialysis sessions. In summary, hemodialysis is "under-delivered" in the United States. Financial and time constraints result in failure to recognize such inadequacy given the infrequent collection of blood for urea samples and calculation of KT/Vd, as well as poor modeling due to variability of the rebound effect and early post dialysis blood collection.
As noted above, monitoring the adequacy of hemodialysis, as defined by the National Kidney Foundation (NKF)--"1997 DOQI Clinical Practice Guidelines for Hemodialysis Adequacy", and the Renal Physicians Associations (RPA) "1993 Clinical Practice Guidelines on Adequacy of Hemodialysis", entail measuring blood urea nitrogen (BUN) pre- and post-dialysis once per month in order to calculate the so-called single pool KT/Vd value with K=dialyzer clearance, T=time of dialysis, and V=volume of distribution of urea. KT/Vd is then calculated from pre- and post-dialysis BUN concentrations by the following formula: EQU KT/V=-Ln(Ct/Co-0.008t-UF/W)
Where Ct is the post-dialysis urea level and Co is the pre-dialysis urea level; t is the time; UF is the ultrafiltrate removed; and W is the post-dialysis weight.
The equation is most representative of the true dialysis dose if the post session BUN blood sample is drawn after the blood urea has equilibrated with the interstitial and intracellular urea. Release of sequestered urea from the intracellular space to the extracellular space continues for 30 to 60 minutes after completion of a dialysis session. This equilibration is due to the removal of urea from the blood by the dialyzer at a rate that exceeds the rate of diffusion from the intracellular to the extracellular compartment. Delays of equilibrium are also caused by the so-called "flow-volume disequilibrium". Seventy percent of the total body water is contained in organs that receive only 20% of the cardiac output. Relatively poorly perfused tissues such as skin, muscle, and bone are cleared of urea less efficiently than highly vascularized organs such as the liver or lungs. The consequence of this compartmentalization of urea is an increase in the BUN concentration over the 60 minutes after the completion of hemodialysis.
The magnitude of the urea rebound varies greatly among dialysis patients. The average increase of urea concentration in the 30 minutes following completion of dialysis is 17%. However, some patients exhibit a rebound as high as 45%. This results in a 75% error between KT/V based on immediate post-dialysis BUN measurement and 30 minutes post-dialysis determination. Despite these limitations of the single-pool KT/V model based on the immediate post-dialysis BUN, the need to obtain the post-dialysis BUN sample 30 to 60 minutes after the completion of dialysis in order to compute the more accurate double-pool KT/V, is impractical in the out-patient hemodialysis setting.
At least two methods for approximating the equilibrated or double-pool KT/Vd have been proposed in the literature. The Smye formula approximates the equilibration BUN concentration based on three urea measurements, the usual pre- and post-dialysis determinations, as well as a mid-dialysis blood sample. This method yields an average error of 13% between the estimated equilibration KT/V and the true equilibrated value. The Daugirdas formulas are based on linear transformations of the single-pool KT/V modified according to the type of vascular access; venous shunt or arterial shunt. The improvement of accuracy is comparable to the Smye method.
Despite limitations of the single pool technique, the NKF recommends its use because of the impracticality of the late measurement of urea in the out-patient setting and the unproven accuracy of the double pool estimates.
Living human tissue and blood is recognized as a dynamic system containing a multitude of components and analyte information that is particularly useful in the medical profession for diagnosing, treating and monitoring human physical conditions. To this end, effort has been directed toward developing methods for non-invasive measurement of tissue and blood constituents using spectroscopy. The spectrographic analysis of living tissue has been focused on the identification of spectral information that defines individual analytes and relating such spectral data to the analyte's concentration. Concentration of these analytes vary with time in an individual patient. Acquiring tissue spectral data with sufficient accuracy for use in diagnosis and treatment has proven difficult. Difficulties in conducting the analysis have been found, which are related to the fact that the tissue system is a complex matrix of materials with differing refractive indices and absorption properties. Further, because the constituents of interest are many times present at very low concentrations, high concentration constituents, such as water, have had a detrimental impact on identifying the low level constituent spectral information and giving an accurate reading of the desired constituent concentration.
Improved methods and apparatus for gathering and analyzing a near-infrared tissue spectra for an analyte concentration are disclosed in commonly assigned U.S. Patent applications and issued patents. U.S. Pat. No. 5,655,530 and U.S. patent application Ser. No. 08/844,501, filed Apr. 18, 1997, entitled "Method for Non-invasive Blood Analyte Measurement with Improved Optical Interface" relate to near-infrared analysis of a tissue analyte concentration which varies with time, with a primary focus on glucose concentrations in diabetic individuals. The methods and apparatus include placing a refractive index-matching medium between a sensor and the skin to improve the accuracy and repeatability of testing. U.S. patent application Ser. No. 09/174,812, filed Oct. 19, 1998, entitled "Method for Non-Invasive Blood Analyte Measurement with Improved Optical Interface" discloses additional improvements in non-invasive living tissue analyte analysis. The disclosure of each of these three applications or patents are hereby incorporated by reference.
U.S. Pat. No. 5,636,633 relates, in part, to another aspect of accurate non-invasive measurement of an analyte concentration. The apparatus includes a device having transparent and reflective quadrants for separating diffuse reflected light from specular reflected light. Incident light projected into the skin results in specular and diffuse reflected light coming back from the skin. Specular reflected light has little or no useful information and is preferably removed prior to collection. U.S. patent application Ser. No. 08/871,366, filed Jun. 9, 1997, entitled "Improved Diffuse Reflectance Monitoring Apparatus", discloses a further improvement for accurate analyte concentration analysis which includes a blocking blade device for separating diffuse reflected light from specular reflected light. The blade allows light from the deeper, inner dermis layer to be captured, rejecting light from the surface, epidermis layer, where the epidermis layer has much less analyte information than the inner dermis layer, and contributes noise. The blade traps specular reflections as well as diffuse reflections from the epidermis. The disclosures of the above patent and application, which are assigned to the assignee of the present application, are also incorporated herein by reference.